Single-cell RNAseq provides insight into altered immune cell populations in human fracture nonunions.

Nonunion describes bone fractures that fail to heal, resulting in the fracture callus failing to fully ossify or, in atrophic cases, not forming altogether. Fracture healing is regulated, in part, by the balance of proinflammatory and anti-inflammatory processes occurring within the bone marrow and surface cell populations. We sought to further understand the role of osteoimmunology (i.e., study of the close relationship between the immune system and bone) by examining immune cell gene expression via single-cell RNA sequencing of intramedullary canal tissue obtained from human patients with femoral nonunions. Intramedullary canal tissue samples obtained by reaming were collected at the time of surgical repair for femur fracture nonunion (n = 5) or from native bone controls when harvesting autologous bone graft (n = 4). Cells within the samples were isolated and analyzed using the Chromium Single-Cell System (10x Genomics Inc.) and Illumina sequencers. Twenty-three distinct cell clusters were identified, with higher cell proportions in the nonunion samples for monocytes and CD14 + dendritic cells (DCs), and lower proportions of T cells, myelocytes, and promyelocytes in nonunion samples. Gene expression differences were identified in each of the cell clusters from cell types associated with osteoimmunology, including CD14 + DC, monocytes, T cells, promyelocytes, and myelocytes. These results provide human-derived gene profiles that can further our understanding of pathways that may be a cause or a consequence of nonunion, providing the clinical rationale to focus on specific components of osteoimmunology. Clinical significance: The novel single-cell approach may lead to clinically relevant diagnostic biomarkers during earlier stages of nonunion development and/or investigation into therapeutic options.

Utility of Plasma Protein Biomarkers and Mid-infrared Spectroscopy for Diagnosing Fracture-related Infections: A Pilot Study.

OBJECTIVES: To compare a large panel of plasma protein inflammatory biomarkers and mid-infrared (MIR) spectral patterns in patients with confirmed fracture-related infections (FRIs) with those in controls without infection. DESIGN: Prospective case-control study. SETTING: Academic, Level 1 trauma center. PATIENTS: Thirteen patients meeting confirmatory FRI criteria were matched to 13 controls based on age, time after surgery, and fracture region. INTERVENTION: Plasma levels of 49 proteins were measured using enzyme-linked immunosorbent assay techniques. Fourier transform infrared spectroscopy of dried films was used to obtain MIR spectra of plasma samples. MAIN OUTCOME MEASUREMENTS: The main outcome measurements included plasma protein levels and MIR spectra of samples. RESULTS: Multivariate analysis-based predictive model developed using enzyme-linked immunosorbent assay-based biomarkers had sensitivity, specificity, and accuracy of 69.2% ± 0.0%, 99.9% ± 1.0%, and 84.5% ± 0.6%, respectively, with platelet-derived growth factor-AB/BB, C-reactive protein, and MIG selected as the minimum number of variables explaining group differences ( P < 0.05). Sensitivity, specificity, and accuracy of the predictive model based on MIR spectra were 69.9% ± 6.2%, 71.9% ± 5.9%, and 70.9% ± 4.8%, respectively, with 6 wavenumbers as explanatory variables ( P < 0.05). CONCLUSIONS: This pilot study demonstrates the feasibility of using a select panel of plasma proteins and Fourier transform infrared spectroscopy to diagnose FRIs. Preliminary data suggest that the measurement of these select proteins and MIR spectra may be potential clinical tools to detect FRIs. Further investigation of these biomarkers in a larger cohort of patients is warranted. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Cytoreductive Surgery with HIPEC is a Safe and Effective Palliative Option in Chemorefractory Symptomatic Peritoneal Metastasis.

INTRODUCTION: The safety and efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in peritoneal metastasis in palliative settings remain poorly investigated and understood. Chemotherapy-refractory patients often present with symptomatic disease. This study investigated the safety and survival outcomes of optimal CRS/HIPEC performed primarily for palliation. METHODS: Palliative CRS/HIPEC was defined as asymptomatic patients who did not respond to three or more lines of chemotherapy, progression on current chemotherapy, and/or any symptomatic disease progression, including ascites, bowel obstruction, and pain. Data collected included demographics, histology, length of stay (LOS), perioperative complications, perioperative mortality, adjuvant chemotherapy use, peritoneal recurrence, overall recurrence, and overall survival. RESULTS: The median number of lines of chemotherapy received prior to CRS/HIPEC was 3.2, and 81% of patients were symptomatic. There were no postoperative deaths and the major complication rate was 22%. Ostomy creation and abdominal wall reconstruction were performed in 24% and 21% of patients, respectively. The median LOS was 11 days and successful palliation was achieved in 97% of patients. Overall survival was 13.5 months and factors associated with prolonged survival included optimal CRS (R1/R2a; p < 0.01) and the use of adjuvant chemotherapy (p < 0.001). Synchronous liver metastasis in the colon cancer subset did not negatively impact survival. CONCLUSION: CRS/HIPEC was performed safely in the palliative setting in patients with symptomatic progressive disease receiving multiple lines of chemotherapy. Median survival exceeded 1 year and factors associated with longer survival were optimal CRS and adjuvant chemotherapy. Liver metastasis did not preclude survival benefit in colon cancer patients. CRS/HIPEC can be considered for palliation but should be performed at high-volume centers.

Patient-Specific Precision Injury Signatures to Optimize Orthopaedic Interventions in Multiply Injured Patients (PRECISE STUDY).

SUMMARY: Optimal timing and procedure selection that define staged treatment strategies can affect outcomes dramatically and remain an area of major debate in the treatment of multiply injured orthopaedic trauma patients. Decisions regarding timing and choice of orthopaedic procedure(s) are currently based on the physiologic condition of the patient, resource availability, and the expected magnitude of the intervention. Surgical decision-making algorithms rarely rely on precision-type data that account for demographics, magnitude of injury, and the physiologic/immunologic response to injury on a patient-specific basis. This study is a multicenter prospective investigation that will work toward developing a precision medicine approach to managing multiply injured patients by incorporating patient-specific indices that quantify (1) mechanical tissue damage volume; (2) cumulative hypoperfusion; (3) immunologic response; and (4) demographics. These indices will formulate a precision injury signature, unique to each patient, which will be explored for correspondence to outcomes and response to surgical interventions. The impact of the timing and magnitude of initial and staged surgical interventions on patient-specific physiologic and immunologic responses will be evaluated and described. The primary goal of the study will be the development of data-driven models that will inform clinical decision-making tools that can be used to predict outcomes and guide intervention decisions.

Single-cell RNA sequencing of intramedullary canal tissue to improve methods for studying fracture repair biology.

The ability to study the bone microenvironment of failed fracture healing may lead to biomarkers for fracture nonunion. Herein the authors describe a technique for isolating individual cells suitable for single-cell RNA sequencing analyses from intramedullary canal tissue collected by reaming during surgery. The purpose was to detail challenges and solutions inherent to the collection and processing of intramedullary canal tissue samples. The authors then examined single-cell RNA sequencing data from fresh and reanimated samples to demonstrate the feasibility of this approach for prospective studies.

A Prospective Clinical Trial Comparing Surgical Fixation Versus Nonoperative Management of Minimally Displaced Complete Lateral Compression Pelvis Fractures.

OBJECTIVE: To compare the early pain and functional outcomes of operative fixation versus nonoperative management for minimally displaced complete lateral compression (LC; OTA/AO 61-B1/B2) pelvic fractures. DESIGN: Prospective clinical trial. SETTING: Two academic trauma centers. PATIENTS: Forty-eight adult patients with LC pelvic ring injuries with <10 mm of displacement were treated nonoperatively and 47 with surgical fixation. Sixty percent of participants were randomized. Seventy-three percent of the fractures were displaced <5 mm, and 71% were LC-1 patterns. INTERVENTION: Operative fixation versus nonoperative management. MAIN OUTCOME MEASUREMENTS: The primary outcome was patient-reported pain using the 10-point Brief Pain Inventory. Functional outcome was measured using the Majeed pelvic score. Outcomes were analyzed using hierarchical Bayesian models to compare the average treatment effect from injury to 12 and 52 weeks postinjury. The probability of the mean treatment benefit exceeding a clinically important difference was determined. RESULTS: The 3-month average treatment effect of surgery compared with nonoperative management was a 1.2-point reduction in pain [95% credible interval (CrI): 0.4-1.9] and an 8% absolute improvement in the Majeed score (95% CrI: 3%-14%). Similar results persisted to 1 year. Patients with initial fracture displacement ≥5 mm experienced a larger reduction in pain (2.2, 95% CrI: 0.9-3.5) compared with those patients with less initial displacement (0.9, 95% CrI: 0.1-1.8). CONCLUSION: On average, surgical fixation likely provides a small improvement in pain and functional outcome for up to 12 months. Patients with ≥5 mm of posterior pelvic ring displacement are more likely to experience clinically important improvements in pain. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Exploring the prognostic and therapeutic utility of expanded mutation profiling in appendix peritoneal metastasis managed with CRS/HIPEC.

INTRODUCTION: Interrogation of cancers with next-generation sequencing (NGS) mutation panels has become widely utilized, identifying prognostic and actionable mutations. This study explored the value of expanded mutation analysis in appendix peritoneal metastases (APM). METHODS: Forty-eight APM patients treated 2013-2018 were retrospectively collected from a registry. Fifty-gene NGS analysis was performed in CLIA approved lab to obtain mutation profiles. All patients underwent cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C. Peritoneal cancer index (PCI), optimal CRS, survival (overall survival [OS] and progression-free survival [PFS]) data were collected. Survival analyses were performed on all APM, high-grade (HG), and low grade (LG) subsets, evaluating the impact of specific mutations on the outcome. RESULTS: Eighty-three percent of APM had a mutation identified. KRAS was most frequent, 65% (88% LG 42% HG) with GNAS identified in 92% of LG-APM. SMAD4 and/or TP53 mutations occurred in 25% of APM with observed decreased OS (46 vs. 81 months p = .0029); worse in HG-APM (26 vs. 49 months p = .0451). SMAD4 was associated with the most significant reduction in PFS in APM (p = .0085). Actionable mutations were identified in 73% of APM patients. CONCLUSIONS: Most frequent mutations were KRAS, TP53, and SMAD4, and actionable mutation detection was common. SMAD4 and TP53 were associated with decreased OS. NGS mutation profiling has potential utility in APM.

Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): The Exploratory Health-Related Quality of Life and Patient-Reported Functional Outcomes of a Multi-Centre 2 × 2 Factorial Randomized Controlled Pilot Trial in Young Femoral Neck Fracture Patients.

PURPOSE: Femoral neck fractures in young patients are typically managed with internal fixation using either cancellous screws or a sliding hip screw (SHS). Although fixation preserves the hip joint, patients are still at risk of complications and poor clinical outcomes which lead to diminished function and health related quality of life (HRQL). The Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) pilot randomized controlled factorial trial evaluated the effect of surgical fixation (cancellous screws vs. SHS) and vitamin D supplementation vs. placebo on patient-reported function and HRQL. METHODS: Patients between the ages of 18-60 years with a femoral neck fracture requiring surgical fixation were eligible. Eligible patients were randomized to receive either a sliding hip screw or cancellous screws for fracture fixation AND vitamin D3 4,000 IU or placebo daily for 6 months. Patient-reported function (Hip Outcome Score) and HRQL (Short Form-12) were assessed at standardized time points in the 12 months following their fixation surgery. Patient-reported function and HRQL were summarized using means, SD, and 95% confidence intervals (CIs), or percentages and counts. Longitudinal data analysis with mixed models was used to explore the effect of treatment group and time on the patient-reported function and HRQL. RESULTS: 86 of the 91 patients randomized into the FAITH-2 pilot study were deemed eligible. There were no significant differences in patient-reported function or HRQL between the treatment groups at 12 months post-fracture. At the 6- and 9-month assessments, a potential benefit in hip function was seen in the cancellous screw group. In all treatment groups, participants reported lower function and HRQL at 12 months post-fracture as compared to their pre-injury assessment. CONCLUSIONS: Few differences were found in function and HRQL among the treatment groups in the FAITH-2 pilot study. Despite modern implants and vitamin D supplementation, neither function nor HRQL returns to baseline in this population. Additional efforts to improve the outcomes of these challenging injuries are still needed. LEVEL OF EVIDENCE: Therapeutic Level II.

Predictors of Improved Early Clinical Outcomes After Elective Implant Removal.

OBJECTIVES: To determine preoperative factors predictive of improvement in pain and function after elective implant removal. We hypothesized that patients undergoing orthopaedic implant removal to relieve pain would have significant improvements in both pain and function. DESIGN: Prospective cohort study. SETTING: Level I Trauma Center. PATIENTS/PARTICIPANTS: One hundred eighty-nine patients were enrolled after consenting for orthopaedic implant removal to address residual pain. One hundred sixty-three were available for 3-month follow-up. MAIN OUTCOME MEASUREMENT: Preoperative and postoperative outcome measures including Patient Reported Outcomes Measurement Information System (PROMIS) scores were compared. Preoperative scores, surgeon prediction of pain improvement, and palpable implants were analyzed as predictors of outcomes. RESULTS: Median PROMIS physical function and pain interference scores and visual analogue scale significantly improved by 6, 8, and 2 points, respectively (P < 0.001 for all). Worse preinjury scores predicted improvement in respective postoperative outcomes (P < 0.001 for all). Surgeon prediction of improvement was associated with improved PROMIS pain interference (P = 0.005), patient subjective assessment of pain improvement (P = 0.03), and subjective percent of pain remaining at 3 months (P = 0.02). Implant superficial palpability was not predictive for any postoperative outcomes. CONCLUSIONS: Although the primary indication for implant removal in this population was pain relief, many patients also had a clinically relevant improvement in physical function. In addition, patients who start with worse global indices of pain and function are more likely to improve after implant removal. This suggests that implant-related pain directly contributes to global dysfunction. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Fixation Using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): The Clinical Outcomes of a Multicenter 2 × 2 Factorial Randomized Controlled Pilot Trial in Young Femoral Neck Fracture Patients.

OBJECTIVE: To assess whether the fixation method and vitamin D supplementation affect the risk of patient-important outcomes within 12 months of injury in nongeriatric femoral neck fracture patients. DESIGN: A pilot factorial randomized controlled trial. SETTING: Fifteen North American clinical sites. PARTICIPANTS: Ninety-one adults 18-60 years of age with a femoral neck fracture requiring surgical fixation. INTERVENTION: Participants were randomized to a surgical intervention (sliding hip screw or cancellous screws) and a vitamin D intervention (vitamin D3 4000 IU daily vs. placebo for 6 months). MAIN OUTCOME MEASUREMENTS: The primary clinical outcome was a composite of patient-important complications (reoperation, femoral head osteonecrosis, severe femoral neck malunion, and nonunion). Secondary outcomes included fracture-healing complications and radiographic fracture healing. RESULTS: Eighty-six participants with a mean age of 41 years were included. We found no statistically significant difference in the risk of patient-important outcomes between the surgical treatment arms (hazard ratio 0.90, 95% confidence interval 0.40-2.02, P = 0.80) and vitamin D supplementation treatment arms (hazard ratio 0.96, 95% confidence interval 0.42-2.18, P = 0.92). CONCLUSIONS: These pilot trial results continue to describe the results of current fixation implants, inform the challenges of improving outcomes in this fracture population, and may guide future vitamin D trials to improve healing outcomes in young fracture populations. Although the pilot trial was not adequately powered to detect treatment effects, publishing these results may facilitate future meta-analyses on this topic. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Investigating the utility of extended mutation analysis in gastrointestinal peritoneal metastasis.

BACKGROUND AND OBJECTIVES: Outcomes for gastrointestinal peritoneal metastases (GI-PM) are worse compared to systemic metastases, with a paucity of data exploring extended mutation profiling. An exploratory mutation analysis in GI-PMs was performed as a "proof of concept" of potential predictive values of profiling in GI-PM and rates of actionable mutations. METHODS: The study included 40 GI-PM patients: 14 low-grade mucinous carcinoma peritonei and 26 HG-PM (12 colons, 10 appendix, 4 small bowels). Demographics, histologies, peritoneal cancer indexes, cytoreduction scores, and survival data were collected. NGS 50-gene mutation profiling was performed on 38 specimens. The association of mutations with survival was evaluated in high-grade PM. RESULTS: KRAS, TP53, and SMAD4 mutations were observed in 61%, 29%, and 8% of cases across all tumor histologies. In 66% cases >1 mutations occurred, associated with decreased survival in HG-PM: 32 vs 73 months, P = .03. TP53 or SMAD4 mutations were associated with decreased survival in HG-PM: 22 vs 48 months, P = .02. Actionable mutations were detected in 70%. CONCLUSION: Actionable mutations were detected at high rates. GI-PMs have similar mutational profiles and TP53, SMAD4, and/or >1 mutation were associate with decreased survival in HG-PM. This data supports the concept of the extended mutation profiling utility in GI-PM warranting further investigation.

Significant Improvement in the Value of Surgical Treatment of Tibial Plateau Fractures Through Surgeon Practice Standardization.

INTRODUCTION: It is unclear whether cost-based decisions to improve the value of surgical care (quality:cost ratio) affect patient outcomes. Our hypothesis was that surgeon-directed reductions in surgical costs for tibial plateau fracture fixation would result in similar patient outcomes, thus improving treatment value. METHODS: This was a prospective observational study with retrospective control data. Surgically treated tibial plateau fractures from 2013 to October 2014 served as a control (group 1). Material costs for each case were calculated. Practices were modified to remove allegedly unnecessary costs. Next, cost data were collected on similar patients from November 2014 through 2015 (group 2). Costs were compared between groups, analyzing partial articular and complete articular fractures separately. Minimum follow-up (f/u) was 1-year. Outcomes data collected include Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF) and pain interference domains, Western Ontario and McMaster Universities Osteoarthritis Index, visual analog pain scale, infection, nonunion, unplanned return to surgery, demographics, injury characteristics, and comorbidities. RESULTS: Group 1 included 57 partial articular fractures and 57 complete articular fractures. Group 2 included 37 partial articular fractures and 32 complete articular fractures. Median cost of partial articular fractures decreased from $1,706 to $1,447 (P = 0.025), and median cost of complete articular fractures decreased from $2,681 to $2,220 (P = 0.003). Group 1 had 55 patients who consented to clinical f/u, and group 2 had 39. Median PROMIS PF score was 40 for group 1 and was 43 for group 2 (P = 0.23). There were no significant differences between the groups for any clinical outcomes, demographics, injury characteristics, or comorbidities. Median f/u in group 1 was 31 months compared with 15 months in group 2 (P < 0.0001). DISCUSSION: We have demonstrated that surgeons can improve value of surgical care by reducing surgical costs while maintaining clinical outcomes.

Fixation Using Alternative Implants for the Treatment of Hip Fractures: The feasibility of a multicenter 2 × 2 factorial randomized controlled trial evaluating surgical treatment and vitamin D supplementation in young femoral neck fracture patients.

OBJECTIVES: To conduct a pilot trial for the Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) protocol to assess feasibility of a definitive trial. DESIGN: Pilot trial. SETTING: Twenty-five clinical sites across North America and Australia were initiated, but enrolment occurred in only 15 North American sites. PATIENTS/PARTICIPANTS: Ninety-one randomized adults aged 18 to 60 years with a femoral neck fracture requiring surgical fixation. INTERVENTION: Eligible patients were randomized to receive surgical treatment (sliding hip screw or cancellous screws) AND nutritional supplementation (4000 IU of vitamin D or placebo) for 6 months postfracture. MAIN OUTCOME MEASUREMENTS: Feasibility outcomes included: clinical site initiation, participant enrolment rate, proportion of participants with complete 12-month follow-up, level of data quality, and rate of protocol adherence (number of randomization errors, crossovers between treatment groups, and daily supplementation adherence). RESULTS: Eighty-six of 91 participants randomized into the pilot trial from 15 North American hospitals were deemed eligible. Four of five primary feasibility criteria were not achieved as we were unable to initiate clinical sites outside of North America and Australia due to feasibility constraints, slow participant enrolment (60 participants recruited over 36 mo), low adherence with daily nutritional supplementation at the 6-week (72.1%), 3-month (60.5%), and 6-month (54.7%) follow-up visits, and a high loss to follow-up rate of 22.1% at 12 months. CONCLUSIONS: Despite not meeting key feasibility criteria, we increased our knowledge on the logistics and anticipated barriers when conducting vitamin D supplementation trials in this trauma population, which can be used to inform the design and conduct of future trials on this topic.

Does Operative Intervention Provide Early Pain Relief for Patients With Unilateral Sacral Fractures and Minimal or No Displacement?

OBJECTIVES: To compare pain after operative versus nonoperative pelvic ring injuries with unilateral sacral fractures. DESIGN: Prospective, multicenter, observational. SETTING: Sixteen trauma centers. PATIENTS/PARTICIPANTS: Skeletally mature patients with pelvic ring injury and minimally displaced unilateral zone 1 or 2 sacral fractures and without anteroposterior compression injuries. MAIN OUTCOME MEASUREMENTS: Pelvic displacement was documented on injury plain radiographs and computed tomography scans; a 10 point Visual Analog Scale (VAS) was used to evaluate pain was obtained in the anterior and posterior pelvic ring during the time of union (12 weeks). RESULTS: One hundred ninety-four patients with unilateral sacral fractures displaced less than 5 mm, mean age of 38.7, and mean Injury Severity Score of 14.5 were included. Ninety-nine percent had lateral compression injuries, and 62% were in zone 1. Seventy-four percent were treated nonoperatively. Nonoperative patients had more zone 1 fractures (71%, P = 0.004). Nonoperative patients reported mean VAS 2.7 points higher in the posterior pelvis (P = 0.01) and 1.9 points higher anteriorly (P = 0.11) 24 hours after injury compared with patients treated operatively. After 3 months, nonoperative patients reported higher VAS scores than operative patients: 4.0 versus 2.9 posteriorly (P = 0.019) and 3.2 versus 2.3 anteriorly (P = 0.035). CONCLUSIONS: For sacrum fractures with minimal or no displacement, slight differences in the VAS were noted within 24 hours after injury or surgery, but limited differences were seen at 3 months for either operatively treated minimally or undisplaced sacrum fractures. It is unknown whether this represents clinical relevance. These differences were below the minimally important clinical difference for VAS scores for other orthopaedic conditions. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Early Immunologic Response in Multiply Injured Patients With Orthopaedic Injuries Is Associated With Organ Dysfunction.

OBJECTIVES: To quantify the acute immunologic biomarker response in multiply injured patients with axial and lower extremity fractures and to explore associations with adverse short-term outcomes including organ dysfunction and nosocomial infection (NI). DESIGN: Prospective cohort study. SETTING: Level 1 academic trauma center. PATIENTS: Consecutive multiply injured patients, 18-55 years of age, with major pelvic and lower extremity orthopaedic injuries (all pelvic/acetabular fractures, operative femur and tibia fractures) that presented as a trauma activation and admitted to the intensive care unit from April 2015 through October 2016. Sixty-one patients met inclusion criteria. INTERVENTION: Blood was collected upon presentation to the hospital and at the following time points: 8, 24, 48 hours, and daily during intensive care unit admission. Blood was processed by centrifugation, separation into 1.0-mL plasma aliquots, and cryopreserved within 2 hours of collection. MAIN OUTCOME MEASUREMENTS: Plasma analyses of protein levels of cytokines/chemokines were performed using a Luminex panel Bioassay of 20 immunologic mediators. Organ dysfunction was measured by the Marshall Multiple Organ Dysfunction score (MODScore) and nosocomial infection (NI) was recorded. Patients were stratified into low (MODS ≤ 4; n = 34) and high (MODS > 4; n = 27) organ dysfunction groups. RESULTS: The MODS >4 group had higher circulating levels of interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1 receptor antagonist (IL-1RA), and monokine induced by interferon gamma (MIG) compared with the MODS ≤4 group at nearly all time points. MODS >4 exhibited lower levels of IL-21 and IL-22 compared with MODS ≤4. Patients who developed NI (n = 24) had higher circulating concentrations of IL-10, MIG, and high mobility group box 1 (HMGB1) compared with patients who did not develop NI (n = 37). CONCLUSIONS: Temporal quantification of immune mediators identified 8 biomarkers associated with greater levels of organ dysfunction in polytrauma patients with major orthopaedic injuries. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Correction: Type V Collagen Induced Tolerance Suppresses Collagen Deposition, TGF-ß and Associated Transcripts in Pulmonary Fibrosis.

[This corrects the article DOI: 10.1371/journal.pone.0076451.].

Support stance in carers of adults with eating disorders: Factors associated with collaborative versus directive approaches.

The support provided by family and friends is integral to patient motivation and clinical outcomes across health care populations. However, little is known about factors that promote or interfere with the type of support offered. OBJECTIVE: This research examined factors associated with collaborative versus directive support among carers of adults with eating disorders. METHOD: Participants were mothers, fathers, partners, friends, and siblings (N = 141) of eating disorder patients in hospital or residential treatment. Two methodologies were used to assess directive and collaborative support stance: a questionnaire of support behaviors and coded responses to clinical vignettes. Measures of interpersonal functioning, psychiatric distress, caregiving experience, and closeness with their loved one were also completed. RESULTS: Although carers rated a collaborative stance as more helpful than a directive stance, 60% of responses to the clinical vignettes were directive. Across both methodologies, collaborative support behaviors were associated with beliefs about helpful support and with a less vindictive and cold interpersonal style. Whereas use of a directive support stance was exclusively associated with negative caregiving experiences, collaborative responses were associated with both positive and negative experiences. DISCUSSION: Although the benefits of collaborative support have been well established, this is the first study to examine factors associated with the use of support stance. Findings suggest a number of ways to help carers create and maintain collaborative relationships, including addressing beliefs and interpersonal style and capitalizing on both positive and negative experiences with their loved one. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:498-505).

Developing and Pilot Testing the Readiness and Motivation Interview for Families in Pediatric Weight Management.

Clinical acumen is often used to assess families' motivation prior to initiating pediatric obesity management due to a lack of available tools. The purpose of this pilot study was to (i) develop and (ii) pilot test the "Readiness and Motivation Interview for Families" (RMI-Family) in pediatric weight management. We conducted 5 focus groups with parents (n = 15), youth with obesity (n = 11), and health care providers (n = 8) to explore perceptions of barriers to making healthy behaviour changes, which led to the creation of the RMI-Family as a semi-structured interview. Five domains (treat foods, overeating, emotional eating, total physical activity, and screen time) emerged from the focus groups to inform the development of the RMI-Family, which was then pilot tested with a sample of youth with obesity and their parents (n = 11 dyads). Interviewers administered the RMI-Family to youth (age 12.8 ± 1.7 years; body mass index [BMI] z-score: 2.71 ± 0.43) and parents (age 47.1 ± 3.7 years; BMI: 33.5 ± 10.1 kg/m(2)). The RMI-Family was feasible to administer, easily understood by families, and may be a useful tool for assessing families' motivation. Research is underway to determine the psychometric properties and utility of the RMI-Family in predicting clinical outcomes in pediatric weight management.

Effectiveness of a peer-delivered dissonance-based program in reducing eating disorder risk factors in high school girls.

OBJECTIVE: This pilot study investigated the feasibility, acceptability, and effectiveness of a peer-led dissonance-based eating disorders (ED) prevention/risk factor reduction program with high school girls. METHOD: Ninth grade girls (n = 50) received the peer-led program within the school curriculum. A quasi-experimental design was used to assess changes in ED risk factors preintervention and postintervention compared with waitlist control. Participants were followed through 3-month follow-up. RESULTS: Peer-leader adherence to an intervention manual tailored for this age group was high. The intervention was rated as highly acceptable, with a large proportion of participants reporting that they enjoyed the program and learned and applied new information. Intervention participants exhibited significantly greater pre-post reductions in a majority of risk-factor outcomes compared to waitlist controls. When groups were combined to assess program effects over time there were significant pre-post reductions in a majority of outcomes that were sustained through 3-month follow-up. DISCUSSION: This pilot study provides tentative support for the effectiveness of using peer leaders to implement an empirically supported ED risk factor reduction program in a high school setting. Additional research is needed to replicate results in larger, better-controlled trials with longer follow-up.

Type V collagen induced tolerance suppresses collagen deposition, TGF-ß and associated transcripts in pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V) immunity in IPF patients. The objective of our study was to determine the specificity of col(V) expression profile and anti-col(V) immunity relative to col(I) in clinical IPF and the efficacy of nebulized col(V) in pre-clinical IPF models. METHODS: Col(V) and col(I) expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U) followed by col(V) nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses. RESULTS: Compared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of col(V) and col(I). Systemic anti-col(V) antibody concentrations, but not of anti-col(I), were higher in IPF patients. Nebulized col(V), but not col(I), prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. Col(V) treatment suppressed systemic levels of anti-col(V) antibodies, IL-6 and TNF-α; and local Il-17a transcripts. Compared to controls, nebulized col(V)-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-α and IFN-γ. In a clinically relevant established fibrosis model, nebulized col(V) decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis (Tgf-ß, Il-1ß, Pdgfb), matrix (Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3) and members of the TGF-ß superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb). CONCLUSIONS: Anti-col(V) immunity is pathogenic in IPF, and col(V)-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- ß-related signaling pathways.